Key result
Ulotaront is unlikely to cause clinically relevant QTc prolongation in patients with schizophrenia, as the upper bound of the 90% CI for ΔΔQTcF remained below 10 ms.
Why the study?
This study evaluated the effects of ulotaront, a novel TAAR1 agonist in development for schizophrenia, on electrocardiogram parameters.
Does ulotaront cause clinically relevant QTc prolongation in subjects with schizophrenia?
RCT (n=60)
randomized
Does ulotaront cause clinically relevant QTc prolongation in subjects with schizophrenia?
A single 150 mg dose of ulotaront does not cause clinically relevant QTc prolongation or other ECG interval abnormalities in patients with schizophrenia.
Answers are grounded in this paper and cite their sources.
Supports cardiac safety for ulotaront in schizophrenia; extends ECG data for TAAR1 agonists in further trials.
This study (NCT04369391) evaluated the effects of ulotaront (SEP‐363856), a novel trace amine‐associated receptor 1 (TAAR1) agonist in development for schizophrenia, on electrocardiogram parameters. Study design was a randomized, single‐dose, three‐period crossover (ulotaront 150 mg, placebo, moxifloxacin 400 mg). Sixty subjects with schizophrenia completed all periods. Ulotaront had no clinically relevant effect on heart rate, PR interval, or QRS duration. In by‐time‐point analysis (secondary analysis), the upper bound of the two‐sided 90% confidence interval for ΔΔQTcF (QT interval corrected for heart rate using Fridericia's formula) was below 10 ms at all time points for ulotaront. In concentration‐QTc analysis (primary analysis), a linear mixed‐effects model with ulotaront and its major metabolite SEP‐383103 was selected as the primary model based on prespecified criteria. Effect on ∆∆QTcF exceeding 10 ms can be excluded within observed ranges of ulotaront and SEP‐383103 plasma concentrations up to ~574 and ~272 ng/mL, respectively. The upper bound of 90% CI for ΔΔQTcF can be predicted to be below 10 ms at the highest anticipated clinical exposure, currently defined as steady‐state mean Cmax at ulotaront 100 mg/day in CYP2D6 poor metabolizers, ~416 and ~211 ng/mL for ulotaront and SEP‐383103, respectively. Assay sensitivity was demonstrated by the QTc effect caused by moxifloxacin. In conclusion, ulotaront is unlikely to cause clinically relevant QTc prolongation in patients with schizophrenia at the anticipated maximum therapeutic dose.
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Tsukada et al. (2023) conducted an RCT in schizophrenia (n=60). ulotaront vs. placebo and moxifloxacin 400 mg was evaluated on concentration-QTc analysis (effect on ∆∆QTcF). Ulotaront is unlikely to cause clinically relevant QTc prolongation in patients with schizophrenia, as the upper bound of the 90% CI for ΔΔQTcF remained below 10 ms.
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